Cigarette smoking remains the most important preventable cause of morbidity and mortality in the U. S. Rates of successful abstinence following formal treatment have remained stagnant at less than 35% over the past decade. Breakthroughs in smoking cessation are likely only wit greater understanding of basic factors underlying nicotine dependence. Tolerance to nicotine is very important to study because it may be related to, and even responsible for, the development of nicotine dependence. This research is devoted to examining tolerance to an array of subjective, behavioral, cardiovascular, and antinociceptive (pain reduction) effects of nicotine in smokers. The present renewal application seeks to extend this line of research to specifically delineate the relationship between nicotine tolerance and dependence. Our first specific aim is to compare responses to nicotine across a broa range of male and female populations varying widely on nicotine dependence to examine whether variability in dependence is associated with concomitant variability in tolerance magnitude. It is predicted that greater dependence will be directly related to greater tolerance (i.e. comparing current dependent smokers vs. ex-smokers or 'nondependent' smokers vs. nonsmokers.) This would link tolerance and dependence and characterize the range of variability in tolerance to nicotine. A second specific aim is to examine changes in responses to nicotine in smokers during monitored week-long smoking cessation to see if eliminating exposure causes dissipation of tolerance and if resumptio of smoking causes reinstatement of tolerance. Such an outcome would indicate that cessation causes rapid resensitization of the body to nicotine's effects, which could help explain quick relapse to smoking after brief nicotine exposure (i.e. 'priming'). The third specific aim is to determine whether magnitude of tolerance prior to smoking cessatio may predict degree of tobacco withdrawal and, more importantly, risk of relapse after cessation in smokers trying to quit permanently. If so, variability in tolerance could explain the differential risk and rate of relapse observed among smokers. These differences or change in toleranc will also be directly related to differences or change in nicotine self- administration in a nicotine choice procedure in order to determine whether tolerance (i.e. decreased sensitivity) promotes increased drug intake, which could then lead to greater dependence. Findings from these studies will clarify the link between tolerance and dependence and lead to more refined assessment of dependence and predictors of successful quitting. Results will also generate important knowledge about changes in adaptation to nicotine during initial cessation and about factors involved in the persistence of smoking behavior, providing new directions for the design of effective interventions for smoking cessation.